A mathematical description of polyglutamated folate kinetics
for human breast carcinoma cells (MCF-7) has been formulated
based upon experimental folate, methotrexate (MTX), purine, and
pyrimidine pool sizes as well as reaction rate parameters
obtained from intact MCF-7 cells and their enzyme isolates. The
schema accounts for the interconversion of highly
polyglutamated tetrahydrofolate, 5-methyl-FH4, 5-10-CH2FH4,
dihydrofolate (FH2), 10-formyl-FH4 (FFH4), and 10-formyl-FH2
(FFH2), as well as formation and transport of the MTX
polyglutamates. Inhibition mechanisms have been chosen to
reproduce all observed non-, un-, and pure competition
inhibition patterns. Steady state folate concentrations and
thymidylate and purine synthesis rates in drug-free intact
cells were used to determine normal folate Vmax values. The
resulting average-cell folate model, examined for its ability
to predict folate pool behavior following exposure to 1 microM
MTX over 21 h, agreed well with the experiment, including a
relative preservation of the FFH4 and CH2FH4 pools. The results
depend strongly on thymidylate synthase (TS) reaction
mechanism, especially the assumption that MTX di- and
triglutamates inhibit TS synthesis as greatly in the intact
cell as they do with purified enzyme. The effects of cell cycle
dependence of TS and dihydrofolate reductase activities were
also examined by introducing G- to S-phase activity ratios of
these enzymes into the model. For activity ratios down to at
least 5%, cell population averaged folate pools were only
slightly affected, while CH2FH4 pools in S-phase cells were
reduced to as little as 10% of control values. Significantly,
these folate pool dynamics were indicated to arise from both
direct inhibition by MTX polyglutamates as well as inhibition
by elevated levels of polyglutamated FH2 and FFH2.

Note: two flow BCs were converted into two downstream
concentration BCs, thus removing the GAR and dUMP state
variables. This dropped the number of ODEs from 21 to 19.

To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.

Le NovèreNicolaslenov@ebi.ac.ukEMBL-EBI

RadivoyevitchTomastxr24@po.cwru.eduCASE western research university

2005-06-29T10:22:41Z2017-05-18T10:55:12Z

Default unit of substance redefined to micromole by comparison with the article. Nicolas Le Novere

Default unit of time redefined to hour by comparison with the article. Nicolas Le Novere